Influence of reversible obesity on eating behavior, blood glucose, and insulin in the rat.
Excessive food intake, resulting in extreme obesity, was induced in rats by electrical stimulation (three 30-min sessions per day for 3 wk) of the lateral hypothalamus (LH). Outside the stimulation sessions no voluntary food intake occurred duringthese weeks. In the subsequent recovery period, accurate records of spontaneous feeding were made. Blood levels of glucose, insulin, and free fatty acids (FFA)were determined during the stimulation period as well as the recovery period. Duringfeeding elicited by electrical stimulation of the LH in the obese phase, there was alarge increase in the glucose level. The insulin level, very high in the intervals between the stimulation sessions, showed no change, a small decline, or a large decrease,respectively, during stimulation in the morning, the afternoon, or the night. If food was withheld during stimulation, there was a large increase in the glucose level and alarge decrease in the insulin level. The first spontaneous meal after the termination of stimulation was extremely postponed, viz, until the glucose and insulin levels returned to normal for the first time. The insulin response to the first spontaneous mealwas exaggerated. Although in the following period (about 10 days) a rapid decrease inbody weight occurred, food intake was only minimal. The insulin level was high and the glucose levelsubnormal during that period. The insulin and glucose levels were normal again only after recovery of normal body weight and food intake. It is tentatively concluded that the regulation of body energy stores (body weight) is achieved through the control of food intake by circulating insulin and glucose levels.


Crystal structure of a voltage-gated sodium channel in two potentially inactivated states.
In excitable cells, voltage-gated sodium (Na(V)) channels activate to initiate action potentials and then undergo fast and slow inactivation processes that terminate their ionic conductance. Inactivation is a hallmark of Na(V) channel function and is critical for control of membrane excitability, but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type Na(V)Ab channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2 Å resolution. Compared to previous structures of Na(V)Ab channels with cysteine mutations in the pore-lining S6 helices (ref. 4), the S6 helices and the intracellular activation gate have undergone significant rearrangements: one pair of S6 helices has collapsed towards the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type Na(V)Ab models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues that are analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains have also shifted around the perimeter of the pore module in wild-type Na(V)Ab, compared to the mutant channel, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in Na(V) channel gating and inactivation. These potential inactivated-state structures provide new insights into Na(V) channel gating and novel avenues to drug development and therapy for a range of debilitating Na(V) channelopathies.


[Carney's triad: a new case].
Carney's triad is a very unusual syndrome, associating three different tumours on the same patient, a young woman generally: a gastric leiomyoblastoma, a pulmonary chondroma and an extra-adrenal paraganglioma. The authors report through the literature review and a new case of Carney's syndrome associating gastric leiomyoblastoma and extra-adrenal paragangliomas, the different diagnostic and therapeutic criterias.


Sodium N-methyl-D-glucamine dithiocarbamate and cadmium intoxication.
The sodium and ammonium salts of N-methyl-D-glucamine dithiocarbamate were prepared and their usefulness as antidotes for cadmium intoxication investigated. This chelating agent was found to be effective in both acute and repeated exposure cadmium poisoning. A single intraperitoneal injection of sodium N-methyl-D-glucamine dithiocarbamate (NaNMG-DTC), administered at a level greater than 1.1 mmol/kg body weight, protects against a normally lethal (greater than 95%) dose of cadmium chloride (10 mg CdCl2/kg body weight) and results in a subsequent dose-dependent decrease in the liver and kidney burdens of cadmium ion. In repeated exposure cadmium intoxication, repeated administration of NaNMG-DTC can result in substantial reductions in both the kidney (71%) and the liver (40%) levels of cadmium. The LD50 of the compound was not determined, but single injections of 26.6 mmol/kg body weight (injectate volume 1.0 ml) are well tolerated in mice.


Elongation of N-acetyllactosamine repeats in diantennary oligosaccharides.
Glycosylated [Asn22]lysozyme has been shown to contain N-acetyllactosamine repeats when expressed in chinese hamster ovary (CHO) cells. We find that the major portion of N-acetyllactosamine repeats are associated with diantennary oligosaccharides. In Lec2 CHO cells, which are deficient in sialylation, glycosylated lysozyme is synthesized with increased contents of N-acetyllactosamine repeats terminating in beta-galactosyl residues. In the Lec2 cells and the parental CHO cell line, Pro 5, only a minor portion of the oligosaccharides in lysozyme are of the triantennary type. Previously, it has been shown that the synthesis of N-acetyllactosamine repeats in Asn-linked oligosaccharides is enhanced by an increase in the activity of the elongating beta-N-acetylglucosaminyl transferase and by the synthesis of beta-1,6-linked antennae. The results with glycosylated lysozyme suggest that glycoproteins bearing diantennary oligosaccharides can contain several N-acetyllactosamine repeats and that the number of the latter can be increased by decreasing the activity of the capping sialyl transferases.


Seasonal differences in the timing of flight between the invasive winter moth and native Bruce spanworm promotes reproductive isolation.
The European winter moth, Operophtera brumata L. (Lepidoptera: Geometridae), was accidentally introduced to North America on at least 4 separate occasions, where it has been hybridizing with the native Bruce spanworm, O. bruceata Hulst, at rates up to 10% per year. Both species are known to respond to the same sex pheromones and to produce viable offspring, but whether they differ in the seasonal timing of their mating flights is unknown. Therefore, we collected adult male moths weekly along 2 transects in the northeastern United States and genotyped individuals using polymorphic microsatellite markers as males of these 2 species cannot be differentiated morphologically. Along each transect, we then estimated the cumulative proportions (i.e., the number of individuals out of the total collected) of each species on each calendar day. Our results indicate that there are significant differences between the species regarding their seasonal timing of flight, and these allochronic differences likely are acting to promote reproductive isolation between these 2 species. Lastly, our results suggest that the later flight observed by winter moth compared to Bruce spanworm may be limiting its inland spread in the northeastern United States because of increased exposure to extreme winter events.


The Influence of Gut Microbiota on the Fecundity of Henosepilachna vigintioctopunctata (Coleoptera: Coccinellidae).
The gut microbiota of insects usually plays an important role in the development and reproduction of their hosts. The fecundity of Henosepilachna vigintioctopunctata (Fabricius) varies greatly when they develop on different host plants. Whether and how the gut microbiota regulates the fecundity of H. vigintioctopunctata was unknown. To address this question, we used 16S rRNA sequencing to analyze the gut microbiomes of H. vigintioctopunctata adults fed on two host plant species (Solanum nigrum and Solanum melongena) and one artificial diet. The development of the ovaries and testes was also examined. Our results revealed that the diversity and abundance of gut microorganisms varied significantly in insects reared on different diets. The gut microbiota of H. vigintioctopunctata raised on the two host plants was similar, with Proteobacteria being the dominant phylum in both groups, whereas Firmicutes was the dominant phylum in the group reared on the artificial diet. The predominant microbiota in the S. nigrum group were Acinetobacter soli and Acinetobacter ursingii (Acinetobacter, Moraxellaceae); Moraxella osloensis (Enhydrobacter, Moraxellaceae); and Empedobacter brevis (Empedobacter, Weeksellaceae). The microbiota in this group are associated with high lipid metabolism. In addition, the beetles' ovaries and testes were more highly developed in the S. nigrum group than in the other two groups. These findings provide valuable information for elucidating the complex roles the gut microbiota play in the fecundity of H. vigintioctopunctata, and may also contribute to developing future novel control strategies involving this economically important pest.


Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria.
Albuminuria is an indicator of cardiovascular risk and renal damage in hypertensive individuals. Chronic renin-angiotensin system (RAS) suppression facilitates blood pressure control and prevents development of new-onset-albuminuria. A significant number of patients, however, develop albuminuria despite chronic RAS blockade, and the physiopathological mechanisms are underexplored. Urinary exosomes reflect pathological changes taking place in the kidney. The objective of this work was to examine exosomal protein alterations in hypertensive patients with albuminuria in the presence of chronic RAS suppression, to find novel clues underlying its development. Patients were followed-up for three years and were classified as: a) patients with persistent normoalbuminuria; b) patients developing de novo albuminuria; and c) patients with maintained albuminuria. Exosomal protein alterations between groups were identified by isobaric tag quantitation (iTRAQ). Confirmation was approached by target analysis (SRM). In total, 487 proteins were identified with high confidence. Specifically, 48 proteins showed an altered pattern in response to hypertension and/or albuminuria. Out of them, 21 proteins interact together in three main functional clusters: glycosaminoglycan degradation, coagulation and complement system, and oxidative stress. The identified proteins constitute potential targets for drug development and may help to define therapeutic strategies to evade albuminuria progression in hypertensive patients chronically treated.


T lymphocyte function in patients with malignant biliary obstruction.
The T lymphocyte function in 59 patients with malignant biliary obstruction undergoing pre-operative endoscopic drainage (group Ia, n = 24) or surgery (group Ib, n = 35) was evaluated by mitogen stimulation test with phytohaemagglutinin. The T lymphocyte function before endoscopic or surgical intervention was found to be impaired as compared with patients with gastric cancer (group II, n = 27) and with normal persons (group III, n = 19). Regression analysis showed a significant negative correlation between T lymphocyte function and the serum bilirubin level (correlation coefficient -0.3, P = 0.01) and a positive correlation with serum albumin level (correlation coefficient 0.34, P = 0.01) and serum transferrin level (correlation coefficient 0.45, P = 0.001). After 18 +/- 3 days of endoscopic biliary drainage, the T lymphocyte function of group Ia patients did not change substantially. At postoperative day 14, there were more patients in both groups Ia and Ib having deterioration of T lymphocyte function than those with improvement. The incidence of postoperative sepsis was found to be significantly higher in patients with deterioration than those with improvement of T lymphocyte function (18/31 vs 7/26, P = 0.036). It is concluded that endoscopic biliary drainage and surgery could not reverse the T lymphocyte dysfunction in patients with malignant biliary obstruction.


The reaction between the bromine atom and the water trimer: high level theoretical studies.
Three different reaction pathways are found for the reaction of bromine atom (Br) with the lowest-energy structure of the water trimer [uud-(H2O)3], initially using the MPW1K-DFT method. The three bromine pathways have closely related geometries and energetics, analogous to those found for the fluorine and chlorine reactions. The lowest-energy pathway of the Br + uud-(H2O)3 reaction was further investigated using the "gold standard" CCSD(T) method and the correlation-consistent basis sets up to cc-pVQZ(-PP). Based on the CCSD(T)/cc-pVQZ(-PP)//CCSD(T)/cc-pVTZ(-PP) results, the Br + (H2O)3 reaction is endothermic by 33.3 kcal mol-1. The classical barrier height is 29.0 kcal mol-1 between the reactants and the exit complex, and there is no barrier for the reverse reaction. The Br⋯(H2O)3 entrance complex is found to lie 4.7 kcal mol-1 below the separated reactants, and the HBr⋯(H2O)2OH exit complex is bound by 6.4 kcal mol-1 relative to the separated products. This potential energy profile is further corrected by the zero point energies and spin-orbit coupling effects. Structurally, the Br + (H2O)3 stationary points can be derived from those of the simpler Br + (H2O)2 reaction by judiciously appending a H2O molecule. The Br + (H2O)3 potential energy profile is compared with the Br + (H2O)2 and Br + H2O reactions, as well as to the valence isoelectronic Cl + (H2O)3 and F + (H2O)3 systems. It is reasonable to expect that the reactions between the bromine atom and larger water clusters would be similar to the Br + (H2O)3 reaction.


The peak shift in stimulus generalization: equivalent effects of errors and noncontingent shock.
Terrace suggested that the peak shift in stimulus generalization occurs because the training stimulus not correlated with reinforcement has become aversive. This hypothesis is plausible in the light of instances where the peak shift is obtained compared with those where it fails to appear. The present experiment attempted to test implications of this hypothesis. Two groups of pigeons learned the same two-stimulus discrimination between colors by different training methods in a free-operant situation. When the discrimination was trained with many errors, a large peak shift was obtained in a subsequent generalization test of wavelength; after discrimination training with few errors, a negligible shift was observed. Half of each group then received noncontingent aversive shock during presentations of the stimulus not correlated with reinforcement in continued discrimination training. After this treatment, the errorless-shock subgroup showed a large peak shift and the error-shock subgroup tended to show a larger shift than before. Nonshocked control groups showed little change in the peak shift. It was concluded that pairing aversive shock with a stimulus not correlated with reinforcement is sufficient to produce or enhance a peak shift. In their effect on the peak shift, aversive shock and large amounts of nonreinforced responding appear to be equivalent.


Factors associated with the direction of ocular deviation in sensory horizontal strabismus and unilateral organic ocular problems.
To evaluate factors associated with the direction of horizontal deviation in the sensory strabismus of patients with unilateral organic amblyopia. The medical charts of 53 patients who had been diagnosed with sensory strabismus between 2000 and 2009 were reviewed retrospectively. The underlying ocular disease, time of onset and the duration of vision impairment, refractive error and axial length of the fixing eye, and the direction and angle of deviation were analyzed to determine the distribution of underlying diseases and any factors relevant to determining the direction of the horizontal deviation. Congenital cataracts were the most common underlying disease, found in 33 patients, followed by acquired cataracts, optic nerve disorders, retinal detachment, glaucoma and lens subluxation. Among the 50 patients with horizontal strabismus, 11 had esotropia and 39 had exotropia. The incidence of esotropia was significantly higher when the fixing eye had hyperopia or emmetropia, than when the eye was myopic. Age of onset of vision deterioration and at diagnosis of sensory strabismus, and the axial length of the fixing eye had no relationship to the direction of horizontal deviation. In addition, the duration of visual impairment had no significant relationship with the direction or extent of horizontal deviation. The most common cause of sensory strabismus was congenital cataracts and the most frequent type of strabismus was exotropia. With respect to the direction of horizontal strabismus, esotropia occurred significantly more often when the refractive error of the fixing eye was hyperopia or emmetropia than when the fixing eye was myopic.


Constant glomerular filtration rate in diabetic nephropathy. Correlation to blood pressure and blood glucose control.
Twenty-one patients with diabetes of type I and diabetic nephropathy with reduced glomerular filtration rate (GFR) were followed prospectively with regard to GFR, proteinuria, blood pressure and glucosylated haemoglobin (HbA1). All patients were on antihypertensive treatment. The mean rate of decline in GFR was only 0.38 ml/month = 4.6 ml/year. In one third of the patients, GFR remained constant at a reduced level for at least 24 months. Mean plasma clearance of 51Cr-EDTA in this group was 48.3 +/- 14.6 ml/min/1.73 m2 body surface at entry and 48.0 +/- 13.6 at the time of evaluation. The patients with constant GFR had significantly less proteinuria and lower systolic as well as mean arterial pressure during the study than patients with falling GFR. They also had significantly lower mean HbA1 and fewer very high HbA1 values than patients who deteriorated. The data thus indicate that a combination of good metabolic control and effective blood pressure control may strongly delay the progression of renal insufficiency in diabetic nephropathy. They also show that low degree of proteinuria is a marker of good prognosis.


Premature senescence and cellular phenotype transformation of mesangial cells induced by TGF-B1.
Transforming growth factor-β1 (TGF-β1) is a polypeptide member of the transforming growth factor β superfamily of cytokines and performs many cellular functions. Its overexpression may lead to renal fibrosis. This study planed to investigate the effects of TGF-β1 on the cell cycle and phenotype of mesangial cells. Rat mesangial cells were cultured together with different concentrations (0, 1, 2, 5, and 10 ng/mL) of TGF-β1 for specified times from 0 min to 72 h. 0 ng/mL TGF-β1 and 0 min served as controls. Cell cycles were assessed by flow cytometry and α-smooth muscle actin expression (α-SMA) protein expression by western blot analysis. All data were presented as Mean ± SD. Statistical analysis was performed by using one-way analysis of variance and correlation analysis. Results were considered significant at p < 0.05. After 15 min of co-culture with different concentrations of TGF-β1, the percentage of mesangial cells in G0/G1 phase was significantly elevated compared to the control (p < 0.05). 12 h co-culture induced cell hyperplasia, 24 h co-culture obvious up-regulation of α-SMA (p < 0.01) and one or two cells' myofibroblast phenotype transition, and 36 h co-culture several cells' phenotype transition. Correlation analysis prompted that the TGF-β1-induced premature aging was time-dependent (p < 0.01). TGF-β1 may induce mesangial cells' premature senescence and myofibroblast-like phenotype transformation time-dependently, which may contribute to the development of early stage of glomerulosclerosis.


CLONAL DIVERSITY IN HIGH-ARCTIC POPULATIONS OF DAPHNIA PULEX, A POLYPLOID APOMICTIC COMPLEX.
Based largely on analogy with latitudinal trends in species diversity, it has been proposed that levels of genotypic (clonal) diversity in parthenogenetic populations from high latitudes should be lower than those in populations from the temperate zone or the tropics. Prior studies have shown that low-arctic populations of obligately asexual Daphnia pulex are less clonally diverse than temperate-zone populations. To test for the existence of a latitudinal trend, an allozymic survey of obligately parthenogenetic populations of D. pulex was conducted at a site in the Canadian high-arctic. The study revealed the presence of 75 clones in 179 tundra ponds that were surveyed. On average, 4.5 clones coexisted in single ponds with a range of 1-14 clones. These diversity values are as great (or greater) than those observed in more southerly populations and conflict with the notion of reduced levels of genetic variation in arctic populations. Mechanisms that may influence genetic (clonal) diversity in apomictic complexes are discussed.


The short metyrapone test in chronic headache patients.
The short, overnight, metyrapone test with plasma ACTH and beta-endorphin (beta-EP) determination has been performed in patients with migraine, other forms of headache, and healthy volunteers. A rise in plasma ACTH and beta-EP after metyrapone occurred in all investigated subjects. The rate of increase varied greatly from one individual to the other, but no significant differences between the mean values of plasma ACTH and beta-EP in different groups of headache patients and volunteers were observed. Three months of nadolol therapy in migraine patients caused a significant increase in plasma ACTH and decrease in beta-EP concentrations. Findings support the view that migraine patients do not have a primary dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis as demonstrated by methods currently in use.


Validation of Electronic Activity Monitor Devices During Treadmill Walking.
The purpose of this study was to assess the validity of the step count measurement of commercial electronic activity monitor devices. Two popular models, Fitbit Charge HR and Mi Band 2, were selected for treadmill walking in a single session. Thirty healthy volunteers walked at five predetermined speeds (0.90, 1.12, 1.33, 1.54, and 1.78 m/s) on a treadmill with both Fitbit Charge HR and Mi Band 2 worn on their dominant hand's wrist. Observers counted the steps, with the aid of taped video, which was taken as the criterion measure for steps. The validity of the electronic activity devices was assessed by (1) Paired sample t test with the criterion measures and (2) Pearson's correlation coefficients and the corresponding p-values were calculated to compare the output of devices with manual step count. In addition, Bland-Altman plots were constructed to visually inspect the data and to assess agreement with the criterion measures. There were no significant differences in step measurement between Fitbit Charge HR and Mi Band 2 with the criterion measures. Besides, there was a very strong agreement between step count measurements obtained using the Fitbit Charge HR (r = 0.99) and the Mi Band 2 (r = 0.99), at five predetermined speeds while comparing with the observed step counts. Both Fitbit Charge HR and Mi Band 2 provided accurate step count measurement in the treadmill walking test.


[Hyperbaric oxygenation in a large hyperbaric chamber (author's transl)].
Hyperbaric Oxygenation has been used routinely with 503 persons (1100 compressions) in a large walk-in hyperbaric chamber. An optimal interdisciplinary teamwork and mastering of the transportation problems by helicopter is mandatory to make this treatment accessible for patients in distant hospitals as an additional conservative management. In 51 operations under pressure (28 congenital heart disease cases) the luxury oxygenation was a protective measure. The procedure can be done safely with plenty of working time.


Determination of s-nitrosothiols in biological fluids by chemiluminescence.
S-nitrosothiols present in nanomolar concentrations in cells and body fluids play an important role in vasodilation, in preventing platelet aggregation, leukocyte adhesion, and for cellular signaling. However, because of the low levels of s-nitrosothiols and interference with other nitric oxide species, reliable assays that measure both high molecular weight and low molecular weight s-nitrosothiols in plasma and red blood cells red blood cells have been difficult to develop. We have previously developed a sensitive method using Cu(II)-ascorbic acid Cu(II)-ascorbic acid at a neutral pH, which was specific for s-nitrosothiols without interference of nitrite or other NOx species. However, due to neutral pH foaming, this method was not suitable for determinations in plasma or red blood cells with high protein content. This method has now been modified by using copper (II) chloride (CuCl(2)) and ascorbic acid in glacial acetic acid. The low pH solves the foaming problem. However, protonation of nitrite under acidic conditions facilitates the formation of s-nitrosothiols. For this method to specifically measure s-nitrosothiols in the sample, the unreacted thiols are blocked by reacting with N-ethylmaleimide and nitrite is blocked by reacting with acidified sulfanilamide before being analyzed by chemiluminescence. Using this method, s-nitrosothiols have been determined in the range of 2 nM to 26 nM (mean ± SE = 10.18±2.1) in plasma and up to 88.1 nM (mean ± SE = 51.27 ± 10.5) in red blood cells.


Comparison of simple sequence repeats in 19 Archaea.
All organisms that have been studied until now have been found to have differential distribution of simple sequence repeats (SSRs), with more SSRs in intergenic than in coding sequences. SSR distribution was investigated in Archaea genomes where complete chromosome sequences of 19 Archaea were analyzed with the program SPUTNIK to find di- to penta-nucleotide repeats. The number of repeats was determined for the complete chromosome sequences and for the coding and non-coding sequences. Different from what has been found for other groups of organisms, there is an abundance of SSRs in coding regions of the genome of some Archaea. Dinucleotide repeats were rare and CG repeats were found in only two Archaea. In general, trinucleotide repeats are the most abundant SSR motifs; however, pentanucleotide repeats are abundant in some Archaea. Some of the tetranucleotide and pentanucleotide repeat motifs are organism specific. In general, repeats are short and CG-rich repeats are present in Archaea having a CG-rich genome. Among the 19 Archaea, SSR density was not correlated with genome size or with optimum growth temperature. Pentanucleotide density had an inverse correlation with the CG content of the genome.


Phosphoproteome of Toxoplasma gondii Infected Host Cells Reveals Specific Cellular Processes Predominating in Different Phases of Infection.
The invasion of Toxoplasma gondii tachyzoites into the host cell results in extensive host cell signaling activation/deactivation that is usually regulated by the phosphorylation/dephosphorylation. To elucidate how T. gondii regulates host cell signal transduction, the comparative phosphoproteome of stable isotope labeling with amino acids in cell culture-labeled human foreskin fibroblast cells was analyzed. The cells were grouped (Light [L], Medium [M], and Heavy [H] groups) based on the labeling isotope weight and were infected with T. gondii for different lengths of time (L: 0 hour; M: 2 hours; and H: 6 hours). A total of 892 phosphoproteins were identified with 1,872 phosphopeptides and 1,619 phosphorylation sites. The M versus L comparison revealed 694 significantly regulated phosphopeptides (436 upregulated and 258 downregulated). The H versus L comparison revealed 592 significantly regulated phosphopeptides (146 upregulated and 446 downregulated). The H versus M comparison revealed 794 significantly regulated phosphopeptides (149 upregulated and 645 downregulated). At 2 and 6 hours post-T. gondii infection, the most predominant host cell reactions were cell cycle regulation and cytoskeletal reorganization, which might be required for the efficient invasion and multiplication of T. gondii. Similar biological process profiles but different molecular function categories of host cells infected with T. gondii for 2 and 6 hours, which suggested that the host cell processes were not affected significantly by T. gondii infection but emphasized some differences in specific cellular processes at this two time points. Western blotting verification of some significantly regulated phosphoprotein phosphorylation sites was consistent with the mass spectra data. This study provided new insights into and further understanding of pathogen-host interactions from the host cell perspective.


The Efficacy and Safety of Intermittent Low-Dose Urokinase Thrombolysis for the Treatment of Senile Acute Intermediate-High-Risk Pulmonary Embolism: A Pilot Trial.
Thrombolysis and anticoagulation were the main treatment methods for acute pulmonary embolism. However, the use of thrombolysis drugs may lead to bleeding complications. We compared intermittent low-dose urokinase (UK) and alteplase (recombinant tissue plasminogen activator [rt-PA]) in normotensive patients with intermediate-high-risk pulmonary embolism. The UK group was treated with intravenous UK 10 000 U/kg once a day for 7 days. The rt-PA group was given alteplase 50 mg by intravenous injection within 2 hours of admission. After thrombolytic therapy, 48 patients were included in this trial. Compared with before treatment, right and left ventricular diastolic diameter ratio, systolic pulmonary artery pressure, and cardiac troponin I of the 2 groups all significantly decreased 8 and 14 days after treatment, which indicated that right heart function improved. Total efficacy rates for the UK group 8 and 14 days after treatment (79.2%, 87.5%) and the rt-PA group (75.0%, 91.67%) were not significantly different. Adverse bleeding reactions were higher in the rt-PA group (20.8%) than in the UK group (8.3%). This pilot study indicates that intermittent low-dose UK thrombolysis is equally effective as rt-PA. However, future large-scale studies must also determine whether small doses of UK thrombolysis reduce the risk of bleeding.


Granting clinical privileges for telerobotic surgery.
Surgeons can now perform operations on their patients while sitting at a remote site. During telerobotic operations, the surgeon sits at a computer console. The computer translates the motions of the surgeon's hands into motions of the robotic instruments. Introduction of telerobotics into clinical practice raises issues comparable to those generated by the rapid introduction of laparoscopic cholecystectomy in the late 1980s. As a result, we have instituted processes in our hospitals for the granting of clinical privileges for telerobotic surgery. These processes are derived from the guidelines of the Society of American Gastrointestinal Endoscopic Surgeons for granting clinical privileges for laparoscopic general surgery. Our hospitals require the following: (1) board certification or board eligibility for the appropriate surgical board; (2) clinical privileges for the open and laparoscopic operations that will be performed telerobotically; (3) satisfactory completion of the Food and Drug Administration-mandated training course in the safe use of the robotic surgical system; (4) performance of telerobotic operations in animate models; (5) observation of clinical cases of telerobotic surgery by an expert surgeon; (6) acting as bedside assistant surgeon in telerobotic operations or supervision by a preceptor during the surgeon's initial operations; (7) observation by a proctor of the surgeon's initial clinical telerobotic operations; and (8) ongoing monitoring of surgical outcomes of telerobotic operations. This process has facilitated the safe and orderly introduction of telerobotics operations into clinical practice in our hospitals.


Minimally invasive parathyroidectomy.
Minimally invasive parathyroidectomy (MIP) is an operative approach for the treatment of primary hyperparathyroidism (pHPT). Currently, routine use of improved preoperative localization studies, cervical block anesthesia in the conscious patient, and intraoperative parathyroid hormone analyses aid in guiding surgical therapy. MIP requires less surgical dissection causing decreased trauma to tissues, can be performed safely in the ambulatory setting, and is at least as effective as standard cervical exploration. This paper reviews advances in preoperative localization, anesthetic techniques, and intraoperative management of patients undergoing MIP for the treatment of pHPT.


A health partnership to reduce neonatal mortality in four hospitals in Rwanda.
A health partnership to improve hospital based neonatal care in Rwanda to reduce neonatal mortality was requested by the Rwandan Ministry of Health. Although many health system improvements have been made, there is a severe shortage of health professionals with neonatal training. Following a needs assessment, a health partnership grant for 2 years was obtained. A team of volunteer neonatologists and paediatricians, neonatal nurses, lactation consultants and technicians with experience in Rwanda or low-income countries was assembled. A neonatal training program was provided in four hospitals (the 2 University hospitals and 2 district hospitals), which focused on nutrition, provision of basic respiratory support with nasal CPAP (Continuous Positive Airway Pressure), enhanced record keeping, thermoregulation, vital signs monitoring and infection control. To identify if care delivery improved, audits of nutritional support, CPAP use and its complications, and documentation in newly developed neonatal medical records were conducted. Mortality data of neonatal admissions was obtained. Intensive neonatal training was provided on 27 short-term visits by 10 specialist health professionals. In addition, a paediatric doctor spent 3 months and two spent 6 months each providing training. A total of 472 training days was conducted in the neonatal units. For nutritional support, significant improvements were demonstrated in reduction in time to initiation of enteral feeds and to achieve full milk feeds, in reduction in maximum postnatal weight loss, but not in days for regaining birth weight. Respiratory support with bubble CPAP was applied to 365 infants in the first 18 months. There were no significant technical problems, but tissue damage, usually transient, to the nose and face was recorded in 13%. New medical records improved documentation by doctors, but nursing staff were reluctant to use them. Mortality for University teaching hospital admissions was reduced from 23.6% in the 18 months before the project to 21.7%. For the two district hospitals, mortality reduced from 10% to 8.1%. A major barrier to training and improved care was low number of nurses working on neonatal units and staff turnover. This health partnership delivered an intensive program of capacity building by volunteer specialists. Improved care and documentation were demonstrated. CPAP was successfully introduced. Mortality was reduced. This format can be adapted for further training and improvement programs to improve the quality of facility-based care.


Public health messages during a global emergency through an online community: a discourse and sentiment analysis.
The growing popularity of social media and its ubiquitous presence in our lives brings associated risks such as the spread of mis- and disinformation, particularly when these may be unregulated in times of global crises. Online communities are able to provide support by enabling connection with others and also provide great potential for dynamic interaction and timely dissemination of information compared with more traditional methods. This study evaluates interactions within the Essex Coronavirus Action/Support Facebook private group, which set out to prevent the spread of COVID-19 infection by informing Essex residents of guidance and helping vulnerable individuals. At the outset, 18 community administrators oversaw the group, which attracted approximately 37,900 members. Longitudinal Facebook group interactions across five periods spanning the UK lockdowns 2020-2021 were analysed using psychological discourse analysis and supplementary computed-mediated analysis to further explore sentiment and linguistic features. The findings endorsed that the group provided a protected space for residents to express their feelings in times of crises and an opportunity to address confusion and concern. The effective communication of public health messages was facilitated by promoting desired interaction and the construction of group identities. Administrators worked with group members to achieve a shared understanding of others' perspectives and the COVID-19 evidence base, which led to a mobilisation of the provision of support in the community. This was accomplished through the application of rhetorical and interactional devices. This study demonstrates how online groups can employ discursive strategies to engage audiences, build cohesion, provide support, and encourage health protective behaviours. This has implications for public health teams in terms of designing, implementing, or evaluating such interventions.


Meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with breast cancer.
The prognostic value of signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 in breast cancer remains controversial in heterogeneous. The objective of this meta-analysis was to evaluate STAT3 and phospho-STAT3 expression on the prognosis of breast cancer patients. PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Chinese CNKI, and Wan Fang were searched up to 19th June 2017. Studies which investigated the STAT3 or phospho-STAT3 expression of patients with breast cancer on the basis of patient survival data or survival curve were eligible. This meta-analysis involves 12 studies and 4513 female patients with breast cancer. No clear relationship exists between overall survival (OS) and high expression of STAT3 and p-STAT3 (hazard ratio [HR] = 0.95, 95% confidence interval [CI]: 0.62-1.46, p > 0.05). p-STAT3 expression is unrelated to disease-free survival (HR = 0.69, 95% CI: 0.18-2.55, p = 0.573). Notably, the pooled effect predicts better breast cancer-specific survival with p-STAT3 overexpression (HR = 0.68, 95% CI: 0.59-0.78, I2 = 30.9%, p < 0.001). Results of subgroup analyses show that STAT3 overexpression indicates shorter OS (HR = 1.87, 95% CI: 1.42-2.45, p < 0.001) when excluding the heterogeneity test. Meanwhile, p-STAT3-positive patients have a significantly higher OS than their counterparts (HR = 0.72, 95% CI: 0.57-0.91, p < 0.01). Positive STAT3 expression may indicate poor OS. However, p-STAT3, as a potential molecular biomarker for predicting chemotherapeutic effect, appears to have better prognostic value than STAT3.


[Subarachnoid hemorrhage without aneurysm on the angiogram: the value of repeat angiography].
To determine the yield of repeated angiography in patients with a non-perimesencephalic subarachnoid haemorrhage (SAH) and a negative first cerebral angiogram. Retrospective. All diagnostic data of patients with a spontaneous SAH admitted to the Department of Neurology, St. Elisabeth Hospital, Tilburg, the Netherlands, in the period 1 January 1992-30 June 2000 were analysed. Patients with a perimesencephalic haemorrhage on a CT-scan were excluded and follow-up was completed. A negative angiogram was considered false-negative, if an aneurysm was shown on a repeat angiogram or after a rebleed. These angiograms were reviewed. A total of 333 patients with a spontaneous SAH were registered. Of these, 249 patients had one or more angiograms made, which resulted in 59 first angiograms being negative (24%). A total of 36 patients had a non-perimesencephalic SAH (26 women and 10 men; mean age: 54 years (range: 25-77)). In 25 of these 36 patients, angiography was repeated revealing 9 aneurysms. Four patients suffered from a rebleed after a previous negative angiogram. Altogether, in 13 of these 36 patients the first negative angiogram was false-negative (36%). In 5 of the 9 patients with a positive repeat angiogram, the first angiogram had been incorrectly assessed as negative. Of the 36 patients with a non-perimesencephalic subarachnoid haemorrhage and a negative angiogram, 13 were revealed to have an aneurysm. Nine of these 13 aneurysms were demonstrated on a repeat angiogram. Technical and interpretation factors appeared to play an important role in missing an aneurysm on a cerebral angiogram.


Naturalness bounds on dipole moments from new physics.
Assuming naturalness that the quantum corrections to the mass should not exceed the order of the observed mass, we derive and apply model-independent bounds on the anomalous magnetic moments and electric dipole moments of leptons and quarks due to new physics.


Physical activity level and fall risk among community-dwelling older adults.
[Purpose] To find the physical activity level and fall risk among the community-dwelling Malaysian older adults and determine the correlation between them. [Subjects and Methods] A cross-sectional study was conducted in which, the physical activity level was evaluated using the Rapid Assessment of Physical Activity questionnaire and fall risk with Fall Risk Assessment Tool. Subjects recruited were 132 community-dwelling Malaysian older adults using the convenience sampling method. [Results] The majority of the participants were under the category of under-active regular light-activities and most of them reported low fall risk. The statistical analysis using Fisher's exact test did not show a significant correlation between physical activity level and fall risk. [Conclusion] The majority of community-dwelling Malaysian older adults are performing some form of physical activity and in low fall risk category. But this study did not find any significant correlation between physical activity level and fall risk among community-dwelling older adults in Malaysia.


Development and validation of a UPLC-MS/MS method for the simultaneous determination of paritaprevir and ritonavir in rat liver.
Determination of paritaprevir and ritonavir in rat liver tissue samples. We successfully validated a UPLC-MS/MS method to measure paritaprevir and ritonavir in rat liver using deuterated internal standards (d8-paritapervir and d6-ritonavir). The method is linear from 20 to 20,000 and 5 to 10,000 pg on column for paritaprevir and ritonavir, respectively, and is normalized per milligram tissue. Interday and intraday variability ranged from 0.591 to 5.33% and accuracy ranged from -6.68 to 10.1% for quality control samples. The method was then applied to the measurement of paritaprevir and ritonavir in rat liver tissue samples from a pilot study. The validated method is suitable for measurement of paritaprevir and ritonavir within rat liver tissue samples for PK studies.


Exploring homologous recombination repair and base excision repair pathway genes for possible diagnostic markers in hematologic malignancies.
Hematologic malignancies (HMs) are a collection of malignant transformations, originating from the cells in the bone marrow and lymphoid organs. HMs comprise three main types; leukemia, lymphoma, and multiple myeloma. Globally, HMS accounts for approximately 10% of newly diagnosed cancer. DNA repair pathways defend the cells from recurrent DNA damage. Defective DNA repair mechanisms such as homologous recombination repair (HRR), nucleotide excision repair (NER), and base excision repair (BER) pathways may lead to genomic instability, which initiates HM progression and carcinogenesis. Expression deregulation of HRR, NER, and BER has been investigated in various malignancies. However, no studies have been reported to assess the differential expression of selected DNA repair genes combinedly in HMs. The present study was designed to assess the differential expression of HRR and BER pathway genes including RAD51, XRCC2, XRCC3, APEX1, FEN1, PARP1, and XRCC1 in blood cancer patients to highlight their significance as diagnostic/ prognostic marker in hematological malignancies. The study cohort comprised of 210 blood cancer patients along with an equal number of controls. For expression analysis, q-RT PCR was performed. DNA damage was measured in blood cancer patients and controls using the comet assay and LORD Q-assay. Data analysis showed significant downregulation of selected genes in blood cancer patients compared to healthy controls. To check the diagnostic value of selected genes, the Area under curve (AUC) was calculated and 0.879 AUC was observed for RAD51 (p < 0.0001) and 0.830 (p < 0.0001) for APEX1. Kaplan-Meier analysis showed that downregulation of RAD51 (p < 0.0001), XRCC3 (p < 0.02), and APEX1 (p < 0.0001) was found to be associated with a significant decrease in survival of blood cancer patients. Cox regression analysis showed that deregulation of RAD51 (p < 0.0001), XRCC2 (p < 0.02), XRCC3 (p < 0.003), and APEX1 (p < 0.00001) was found to be associated with the poor prognosis of blood cancer patients. Comet assay showed an increased number of comets in blood cancer patients compared to controls. These results are confirmed by performing the LORD q-assay and an increased frequency of lesions/Kb was observed in selected genes in cancer patients compared to controls. Our results showed significant downregulation of RAD51, XRCC2, XRCC3, APEX1, FEN1, PARP1, and XRCC1 genes with increased DNA damage in blood cancer patients. The findings of the current research suggested that deregulated expression of HRR and BER pathway genes can act as a diagnostic/prognostic marker in hematologic malignancies.


Health influence of SARS-CoV-2 (COVID-19) on cancer: a review.
The novel coronavirus, namely, SARS-CoV-2 (COVID-19), broke out two years ago and has caused major global health issues. Adequate treatment options are still lacking for the management of COVID-19 viral infections. Many patients afflicted with COVID-19 may range from asymptomatic to severe symptomatic, triggering poor clinical outcomes, morbidity, and mortality. Cancer is one of the leading causes of death worldwide. It is pertinent to re-examine cancer prevalence during the COVID-19 pandemic to prevent mortality and complications. Understanding the impact of SARS-CoV-2 on cancer is key to appropriate healthcare measures for the treatment and prevention of this vulnerable population. Data was acquired from PubMed using key search terms. Additional databases were utilized, such as the Centers for Disease Prevention and Control, American Cancer Society (ACS), and National Cancer Institute (NCI). Cancer patients are more prone to SARS-CoV-2 infection and exhibit poor health outcomes, possibly due to a chronic immunosuppressive state and anticancer therapies. Male sex, older age, and active cancer disease or previous cancer are risk factors for COVID-19 infection, leading to possible severe complications, including morbidity or mortality. The speculated mechanism for potentially higher mortality or COVID-19 complications is through reduced immune system function and inflammatory processes through cancer disease, anticancer therapy, and active COVID-19 infection. This review includes prostate, breast, ovarian, hematologic, lung, colorectal, esophageal, bladder, pancreatic, cervical, and head and neck cancers. This review should help better maintain the health of cancer patients and direct clinicians for COVID-19 prevention to improve the overall health outcomes.


Hawkmoth and bee pollinators impact pollen dispersal at the landscape but not local scales in two species of Oenothera.
Animal pollinators play an important role in pollen dispersal. Here, we assessed differences in pollen and seed dispersal and the role of pollinator functional groups with different foraging behaviors in generating patterns of genetic diversity over similar geographic ranges for two closely related taxa. We focused on two members of Oenothera section Calylophus (Onagraceae) that co-occur on gypsum outcrops throughout the northern Chihuahuan Desert but differ in floral phenotype and primary pollinator: Oenothera gayleana (bee) and O. hartwegii subsp. filifolia (hawkmoth). We measured breeding system and floral traits and studied gene flow and population differentiation at the local (<13 km; four populations) and landscape (60-440 km; five populations) scales using 10-11 nuclear (pollen dispersal) and three plastid (seed dispersal) microsatellite markers. Both taxa were self-incompatible and floral traits were consistent with expectations for different pollinators. Seed and pollen dispersal patterns were distinctly different for both species. We found no evidence of genetic structure at the local scale but did at the landscape scale; O. gayleana showed greater differentiation and significant isolation by distance than in O. hartwegii subsp. filifolia. The plastid data were consistent with gravity dispersal of seeds and suggest that pollen dispersal is the principal driver of genetic structure in both species. We demonstrated that pollinator functional groups can impact genetic differentiation in different and predictable ways. Hawkmoths, with larger foraging distances, can maintain gene flow across greater spatial scales than bees.


THE MIXED-MODEL ANALYSIS OF VARIANCE APPLIED TO QUANTITATIVE GENETICS: BIOLOGICAL MEANING OF THE PARAMETERS.
The mixed-model factorial analysis of variance has been used in many recent studies in evolutionary quantitative genetics. Two competing formulations of the mixed-model ANOVA are commonly used, the "Scheffe" model and the "SAS" model; these models differ in both their assumptions and in the way in which variance components due to the main effect of random factors are defined. The biological meanings of the two variance component definitions have often been unappreciated, however. A full understanding of these meanings leads to the conclusion that the mixed-model ANOVA could have been used to much greater effect by many recent authors. The variance component due to the random main effect under the two-way SAS model is the covariance in true means associated with a level of the random factor (e.g., families) across levels of the fixed factor (e.g., environments). Therefore the SAS model has a natural application for estimating the genetic correlation between a character expressed in different environments and testing whether it differs from zero. The variance component due to the random main effect under the two-way Scheffe model is the variance in marginal means (i.e., means over levels of the fixed factor) among levels of the random factor. Therefore the Scheffe model has a natural application for estimating genetic variances and heritabilities in populations using a defined mixture of environments. Procedures and assumptions necessary for these applications of the models are discussed. While exact significance tests under the SAS model require balanced data and the assumptions that family effects are normally distributed with equal variances in the different environments, the model can be useful even when these conditions are not met (e.g., for providing an unbiased estimate of the across-environment genetic covariance). Contrary to statements in a recent paper, exact significance tests regarding the variance in marginal means as well as unbiased estimates can be readily obtained from unbalanced designs with no restrictive assumptions about the distributions or variance-covariance structure of family effects.


Improved Biopsy Accuracy in Retroperitoneal Dedifferentiated Liposarcoma.
Biopsy sensitivity in retroperitoneal dedifferentiated liposarcoma (DDLPS) is variable. Patients with grade 3 DDLPS face a significant risk of metastatic disease and may potentially benefit from neoadjuvant therapy, making highly accurate pretherapy diagnosis essential. Our study aimed to establish whether diagnostic sensitivity could be improved by targeting solid areas of tumor on percutaneous biopsy. Between 2016 and 2019, data on patients with suspected primary retroperitoneal sarcoma who underwent a biopsy were collected, and diagnostic accuracy was calculated. These data were compared with our previously reported series from 2005 to 2016. For DDLPS tumors, comparisons were then made between biopsies that targeted the solid component and those that did not. Data were available for 121 patients in the current series and 238 from the previous study. The proportion of biopsies returning a histological subtype concordant with postoperative pathology was 83% in the current series, marking a significant improvement over our previous study (67%, p = 0.001). For diagnosis of DDLPS, biopsy sensitivity improved from 40 to 74% (p < 0.001), with an increase from 13 to 50% (p = 0.006) where grade 3 DDLPS was treated as a separate disease. Within the current series, targeted biopsy yielded a sensitivity of 100% for identifying DDLPS, compared with 10% in nontargeted biopsy (p < 0.001). Systematic targeting of solid areas of tumor within suspected retroperitoneal liposarcoma has improved sensitivity for detection of both DDLPS and grade 3 DDLPS on biopsy. This approach minimizes the risk of underdiagnosis of patients with DDLPS who could benefit from neoadjuvant chemotherapy.


Methanolysis of ammonia borane by shape-controlled mesoporous copper nanostructures for hydrogen generation.
Diverse mesoporous CuO nanostructures have been prepared by a facile and scaleable wet-chemical method and reduced to mesoporous Cu nanostructures by using the reductant ammonia borane (AB). These mesoporous Cu nanostructures have been applied as a catalyst for hydrogen generation from the methanolysis of AB. The catalytic results show that the reaction rate and the amount of hydrogen evolution significantly relied on their morphologies. Compared with the nanosheet-like, bundle-like and dandelion-like Cu, the flower-like Cu nanostructures exhibit the highest catalytic activity with a total turnover frequency (TOF) value of 2.41 mol H2 mol catalyst(-1) min(-1) and a low activation energy value of 34.2 ± 1.2 kJ mol(-1) at room temperature. Furthermore, the flower-like Cu nanostructures have also shown excellent activity in recycling tests. The low cost and high performance of Cu nanocatalysts may offer high potential for its practical application in hydrogen generation from the methanolysis of AB.


[Colonic stenosis following necrotizing enterocolitis in newborn infants. Apropos of 3 cases].
Three cases of double left colic stenosis revealed at one month of age by subobstruction are reported. Recovery was obtained by surgery. The evolution of radiological data in one case, and of histological changes observed on the resected sigmoid colon in the two other cases favor the assumption that cicatricial stenosis occurred likewise. These cases also confirm the existence of a benign expression of necrotising enterocolitis, most common with a colonic localization. Such stenosis due to submucous connective sclerosis strengthens the hypothesis that a transitory mesenteric ischemia is responsible for the necrotizing enterocolitis in newborns.


Survival study of enterotoxigenic Escherichia colistrain in seawater and wastewater microcosms.
In order to survey osmotic and oligotrophic stress consequence on pathogenic enterobacteria discharged in marine areas, we examined enterotoxigenic Escherichia coli (ETEC) and a reference (Ecoli O126:B16) strains during their survival (47 days) in wastewater microcosms, submerged in natural seawater and maintained in laboratory conditions. The results revealed that the survival time for the two strains was prolonged when bacterial cells were previously incubated in wastewater, with less cellular membrane damage. In addition, the wild clinical E. coli strain showed a better survival capacity than the reference E. coli strain one. For both, we noted some modifications in biochemical profiles relatively to the initial state, notably when they were previously incubated in wastewater microcosm.


Significance of Endolymphatic Hydrops Herniation Into the Semicircular Canals Detected on MRI.
The objective of this study was to investigate the relationship between endolymphatic hydrops (EH) and hearing level or vestibular symptoms by focusing on EH herniation into the semicircular canal (SCC). Retrospective study. University hospital. The study included 1,548 ears of 775 patients who underwent magnetic resonance imaging (MRI) examination in our university hospital to investigate possible EH. MRI was performed 4 hours after intravenous injection of a standard dose of gadodiamide hydrate and/or 24 hours after intratympanic injection of gadopentetate dimeglumine diluted eightfold. The hearing threshold and vestibular symptoms were compared between ears with unilateral and bilateral EH herniation into the SCC and between ears having vestibular EH adjacent to the stapes footplate with or without EH herniation. Forty-four ears (19 men and 25 women, mean age 53.6 yr) showed EH herniation into the SCC. The average hearing thresholds at 500 to 4000 Hz and presence of vestibular EH adjacent to the stapes footplate were significantly higher in ears with unilateral herniation than in those with bilateral herniation. The average hearing thresholds at 500 and 1000 Hz were significantly higher in the group of ears having adjacency with herniation than in those without herniation. Vestibular symptoms did not differ significantly between groups. Unilateral herniation occurs with EH progression. Bilateral herniation may occur regardless of EH progression and might be influenced by other factors that alter the membranous labyrinth.


Compensatory response of the luteinizing-hormone (LH)-releasing hormone (LHRH)/LH pulse generator after administration of a potent LHRH antagonist in the ram.
It is established that the blockade of the pituitary LHRH receptor by an LHRH antagonist will suppress pituitary LH secretion and reduce serum concentrations of gonadal steroids. Little is known, however, about the activity of the LHRH/LH pulse generator during this inhibitory period or during the recovery phase. To investigate this, a potent LHRH antagonist [N-Ac-D-pCl-Phe1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6, D-Ala10 LHRH was injected iv into sexually active rams and the changes in the blood plasma concentrations of LH, FSH, testosterone, and PRL were measured in samples collected every 15 min for 24-48 h. The treatment induced an immediate blockade of pulsatile LH secretion and a parallel decline in blood levels of testosterone. Plasma levels of FSH were not suppressed by treatment with the LHRH antagonist and there was no consistent effect on plasma levels of PRL. The duration of the inhibition of LH was dose dependent lasting 4.3 +/- 0.4 h, 18.0 +/- 1.0 h, and 31.8 +/- 1.3 h for the low (6 micrograms/kg), medium (36 micrograms/kg), and high (365 micrograms/kg) doses of LHRH antagonist, respectively. During the recovery period there was an approximate 2-fold increase in the frequency of LH pulses. These results suggest a compensatory response to the decline in the negative feedback effect of testosterone secretion. Even the lowest dose of antagonist elicited a decrease in the level of testosterone and an increase in LH pulse frequency. At this dose, the decline in testosterone was very transitory indicating an acute sensitivity of the hypothalamus to changes in the negative feedback signal. These results suggest that the suppression of LH and testosterone secretion in the ram by LHRH antagonist is associated with a compensatory increase in the activity of the LHRH pulse generator.


[Clinical guidelines for the diagnosis and treatment of pulmonary hypertension].
Pulmonary hypertension (PH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, which results in right ventricular heart failure and sudden death. Based on the current version of the guidelines for PH diagnosis and treatment, adopted by the experts of the European Society of Cardiology and the European Respiratory Society in 2009, and on the data of Russian and foreign clinical trials, the Russian experts elaborated clinical guidelines for PH in 2013. The latter consider the current classifications of PH, the specific features of its pathogenesis, and its diagnostic algorithm. The section dealing with drugs for maintenance therapy discusses data on the use of oral anticoagulants, diuretics, cardiac glycosides, and oxygen therapy. PH-specific therapy includes calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Surgical procedures for PH involve atrial septostomy, thromboendartectomy, and lung or heart-lung transplantation. A treatment algorithm is proposed for PH patients. The current medicinal approaches using specific therapy agents and their combinations offer new promises for the effective treatment of patients with PH and improve its prognosis.


Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients.
Iron-overload-associated cardiomyopathy has been one of the primary causes of mortality in thalassemia patients with iron burden. There is growing evidence citing the beneficial effects of ebselen as an antioxidant selectively blocking the divalent metal transporter 1 (DMT-1) to deter iron ingress into cardiomyocytes, raising internets in viewing this component in this population in order to treat and even prevent cardiomyopathy occurring from iron surplus. In this article, we reviewed the potential advantageous effects of ebselen in thalassemia patients who suffer from iron excess, susceptible to cardiomyopathy induced by iron overload. A systematic search in several databases, including PubMed, Scopus, and Web of Science, was conducted to explore the role of ebselen in controlling iron-overload-related cardiomyopathy in thalassemia patients by the keywords of Ebselen AND iron. The inclusion criteria were English-written preclinical and clinical studies investigating the efficacy and side effects of ebselen in an iron-overload context. After searching the databases, 44 articles were found. Next, of 19 published articles, 3 were included in this article. After reviewing the references of the included studies, no articles were added. In conclusion ebselen can be a promising adjuvant therapy in patients with thalassemia alongside the standard treatment with iron chelators, particularly in severe cases with cardiomyopathy, due to falling iron inflow by inhibiting DMT-1 and increasing ferroportin-1 expression and antioxidant properties. However, clinical studies need to be carried out to reach a definite conclusion.


Well-defined star-shaped conjugated macroelectrolytes as efficient electron-collecting interlayer for inverted polymer solar cells.
A star-shaped monodisperse conjugated macroelectrolyte grafted with cationic side chains, TrNBr, was designed, synthesized, and utilized as efficient electron-collecting cathode interlayers for inverted polymer solar cells. A neutral one composed of identical star-shaped conjugated backbone, TrOH, was also investigated for comparison. The surface properties and the function as interfacial layers on modulating the work function of bottom electrode (indium tin oxide) were systematically studied. Both interfacial electron-selective materials show strongly thickness-dependent performance for inverted polymer solar cells, and the best performance could be achieved via optimizing the thickness with 2.4 nm of TrNBr and 8.7 nm of TrOH. Parallel investigations of optimized TrNBr and TrOH interlayer in inverted architecture with active blend layer of poly(3-hexylthiophene):indene-C60 bisadduct (P3HT:ICBA) demonstrated a remarkable power conversion efficiency (PCE) enhancement (PCE of 4.88% for TrNBr and 4.74% for TrOH) in comparison with those of conventional noninverted devices using Ca/Al cathodes (3.94%) and inverted devices with sol-gel ZnO buffer layer (4.21%). In addition, the inverted devices using the TrNBr and TrOH interlayer exhibited improved device stability in contrast to conventional noninverted devices using Ca/Al cathodes.


IOP change undergoing anesthesia in rhesus macaques (Macaca mulatta) with laser-induced ocular hypertension.
The objective of the study was to examine changes of intraocular pressure (IOP) undergoing anesthesia in Rhesus Macaques (Macaca mulatta) with Laser-induced Ocular Hypertension. Twenty male rhesus macaques (hypertensive glaucoma eye in OD; normal eye in OS) between 6 and 20 years of age were used for the study. The monkeys were anesthetized with ketamine hydrochloride (10 mg/kg intramuscularly) and 1% isoflurane, and then IOP in both eyes was measured by a single investigator using a calibrated Tonopen(TM) applanation tonometer (Mentor, Norwell, MA, U.S.A.). The mean IOP with ketamine anesthesia was 36.70 ± 12.04 (right eye: OD) and 15.88 ± 2.84 (left eye: OS). The mean IOP with isoflurane anesthesia was 19.98 ± 6.67 (right eye: OD) and 15.32 ± 2.15 (left eye: OS). Undergoing isoflurane anesthesia, the IOP of OD was significantly decreased. Conclusively, careful examination of IOP is required to prevent unexpected contraindication on glaucoma patient with isoflurane anesthesia.


Correlation between the sexually dimorphic aromatase of the preoptic area and sexual behavior in quail: effects of neonatal manipulations of the hormonal milieu.
The aromatase of the preoptic area is significantly more active in males than in females. This sex dimorphism in enzyme activity is still found in birds that have been gonadectomized and treated with a same dose of testosterone. This suggests that the sex difference is not the result of a differential activation by the adult hormonal environment but rather is organized neonatally by steroid hormones. As the central aromatization of testosterone is a limiting step in the activation of copulatory behavior by testosterone, the lower aromatase activity in the preoptic area of females might be responsible, at least in part, for their lower sensitivity to the activating effects of testosterone on behavior. Three experiments were carried out to determine whether early manipulations of the hormonal environment, which are known to differentiate sexual behavior, also affect in a permanent way the aromatase activity in the preoptic area. Injection of estradiol benzoate into male embryos on day 9 of incubation decreased the preoptic aromatase activity in parallel to its demasculinizing effect on behavior. Unexpectedly the same treatment tended to increase enzyme activity in females so that the physiological relevance of the observed enzymatic change remains questionable. In two independent experiments, we confirmed that neonatal ovariectomy of female quail interferes with their behavioral differentiation. Females gonadectomized at 4 days post-hatch showed significantly more male-type sexual behavior as adult in response to testosterone than females gonadectomized at the age of 5 weeks. These experiments also confirmed that the preoptic aromatase activity is higher in males than in females but no evidence for an effect of the age of gonadectomy on the enzyme activity could be obtained. The sex difference and experimental modifications observed in the aromatase activity of the preoptic area were not seen in the posterior hypothalamus demonstrating that these effects are specific. The mechanisms controlling the sex difference in aromatase activity are discussed. The difference might be organized by the action of embryonic steroids as suggested by the changes observed in males injected with estradiol benzoate in egg. Alternatively, activational mechanisms cannot be ruled out at present. In one experiment, the activity of the preoptic aromatase was positively correlated with the sexual activity of the birds.(ABSTRACT TRUNCATED AT 400 WORDS)


Expression of C-IAP1, C-IAP2 and SURVIVIN discriminates different types of lymphoid malignancies.
(De-)regulation of apoptosis plays an important role in normal and malignant lymphopoiesis. Apoptosis-regulating genes of the BCL-2 family and the recently identified inhibitors of apoptosis (IAP) family have been implicated in different types of non-Hodgkin lymphoma (NHL). To investigate whether expression of specific apoptosis-regulating genes correlated with different types of lymphoid malignancies, we measured the expression of five BCL-2 family genes, four IAP family genes and SMAC by real-time quantitative polymerase chain reaction in patient samples. In total, 137 samples from B- and T-cell acute lymphoblastic leukaemia (ALL), B-cell chronic lymphocytic leukaemia (CLL), six different NHL types and three control tissue types were analysed. The data were further analysed using cluster and discriminant analysis. Three specific expression patterns were identified for CLL, ALL and NHL respectively. CLL samples, as well as B-ALL and follicular lymphoma samples showed high similarity in the expression of these apoptosis-regulating genes and could be distinguished from each other and other diseases and controls. Discriminant analysis identified three members of the IAP family, C-IAP1, C-IAP2 and SURVIVIN, as the most informative genes to discriminate between these lymphoid malignancies.


Effects of 12-week brisk walking training on exercise blood pressure in elderly patients with essential hypertension: a pilot study.
Essential hypertension (EP) is characterized by blood pressure (BP) elevations, which often lead to target organ damage and cardiovascular illness. The following study investigates whether aerobic exercise programs with different intensities could reduce the magnitude of BP rise. Patients with essential hypertension were recruited from the Baoshan Community Health Service Center. A total of 46 patients were finally selected and randomly assigned into two groups: control group (CON) included patients who did not participate in exercise intervention training; treatment group (TRG) included patients who participated in 12-week brisk walking training (60-min of brisk walking, three times a week for a total of 12 weeks). 3-minute step tests of low and high intensity were conducted pre- and post-intervention. To compare the effects of exercise intervention, 23 subjects with normal blood pressure (NBP) who did not participate in 12-week brisk walking training, were recruited. After 12 weeks of brisk walking, SBP of TRG during resting, low and high-intensity exercise was significantly reduced by 8.3mmHg, 15.6mmHg, and 22.6mmHg, respectively; while HR of TRG's during resting, low and high intensity was significantly reduced by 3.6beats/minute, 8.7beats/minute and 11.3beats/minute, respectively. Meanwhile, after 12 weeks of brisk walking, TRG's steps per day, [Formula: see text]o2max, moderate physical activity time and physical activity energy expenditure significantly increased by 6000 steps, 2.4 ml/kg/m, 40 minutes and 113 kcal, respectively. At the same time, TRG's body fat rate and sedentary time significantly reduced by 2% and 60 minutes per day. Brisk walking can reduce the magnitude of BP rise during exercise of different intensities and may be reduced the risk of acute cardiovascular incidents in elderly patients with essential hypertension. EP: Essential hypertension; BP: blood pressure; CON: control group; TRG: treatment group; NBP: normal blood pressure; PA: physical activity.


Comparing Naturalistic Mental Health Expressions on Student Loan Debts Using Reddit and Twitter.
The primary objective of this study was to identify patterns in users' naturalistic expressions on student loans on two social media platforms. The secondary objective was to examine how these patterns, sentiments, and emotions associated with student loans differ in user posts indicating mental illness. Data for this study were collected from Reddit and Twitter (2009-2020, n = 85,664) using certain key terms of student loans along with first-person pronouns as a triangulating measure of posts by individuals. Unsupervised and supervised machine learning models were used to analyze the text data. Results suggested 50 topics in reddit finance and 40 each in reddit mental health communities and Twitter. Statistically significant associations were found between mental illness statuses and sentiments and emotions. Posts expressing mental illness showed more negative sentiments and were more likely to express sadness and fear. Patterns in social media discussions indicate both academic and non-academic consequences of having student debt, including users' desire to know more about their debts. Interventions should address the skill and information gaps between what is desired by the borrowers and what is offered to them in understanding and managing their debts. Cognitive burden created by student debts manifest itself on social media and can be used as an important marker to develop a nuanced understanding of people's expressions on a variety of socioeconomic issues. Higher volumes of negative sentiments and emotions of sadness, fear, and anger warrant immediate attention of policymakers and practitioners to reduce the cognitive burden of student debts.


Immigrant women living homeless in Madrid (Spain).
Homeless people are one of the most obvious embodiments of the phenomenon of social exclusion, and homeless immigrants and homeless women are considered 2 particularly vulnerable groups. The objective of this article is to analyze the differences between women living homeless born in Spain (nonimmigrants) and those born abroad (immigrants). The study was carried out based on the data obtained from a sample of women living homeless in Madrid (Spain; N = 136). The information was collected using a structured interview. The results show major similarities between immigrant and nonimmigrant homeless women in terms of their basic sociodemographic characteristics (age, marital status, number of children), their state of health, satisfaction with their family and/or partner relationships, and feelings of loneliness or abandonment. Fewer immigrant women had their documentation in order, they received fewer financial benefits and their contact with their family of origin was more limited. However, the immigrant women became homeless at an older age and were subject to less chronic homelessness, their levels of consumption of alcohol and other psychoactive substances were lower, they had experienced fewer stressful life events, more of them had completed higher education, and more of them used mobile telephones and the Internet. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Interaction of 9-beta-D-arabinofuranosyladenine, 9-beta-D-arabinofuranosyladenine 5'-monophosphate, and 9-beta-D-arabinofuranosyladenine 5'-triphosphate with S-adenosylhomocysteinase.
9-beta-D-Arabinofuranosyladenine (ara-A), 9-beta-D-arabinofuranosyladenine 5'-monophosphate, and 9-beta-D-arabinofuranosyladenine 5'-triphosphate competitively inhibit both the synthesis and hydrolysis of S-adenosylhomocysteine catalyzed by S-adenosylhomocysteinase [S-adenosylhomocysteine hydrolase (EC 188.8.131.52)] from mouse liver, and the inhibitor constants were 5.0 X 10(-6), 1.1 X 10(-4), and 1.0 X 10(-3) M, respectively. A time-dependent inactivation of the enzyme was observed when the enzyme was preincubation with ara-A, 9-beta-D-arabinofuranosyladenine 5'-monophosphate, or 9-beta-D-arabinofuranosyladenine 5'-triphosphate. ara-A was the most potent inactivator. The inactivation with ara-A was less pronounced in the presence of adenosine, S-adenosylhomocysteine, adenine, adenosine 5'-monophosphate, or adenosine 5'-diphosphate, showed first-order kinetics, saturability, and irreversibility. The rate of inactivation was half-maximal at 5 X 10(-6) M ara-A, and the rate constant of inactivation was 0.43 min-1 at saturating concentrations of ara-A. ara-A was tightly but not covalently bound to the enzyme. ara-A bound to the enzyme was not available for deamination to 9-beta-D-arabinofuranosylhypoxanthine catalyzed by the enzyme adenosine deaminase.


One-Dimensional Electrophoresis Using Nondenaturing Conditions.
Electrophoresis is used to separate complex mixtures of proteins (e.g., from cells, subcellular fractions, column fractions, or immunoprecipitates), to investigate subunit composition, track post-translational modifications, and verify identity and homogeneity of protein samples. It can also serve to purify proteins for use in further applications. In polyacrylamide gel electrophoresis, proteins migrate in response to an electrical field through pores in a polyacrylamide gel matrix; pore size decreases with increasing acrylamide concentration. Nondenaturing or "native" electrophoresis-i.e., electrophoresis in the absence of denaturants such as detergents and urea-is an often-overlooked technique for determining the native size, subunit structure, and optimal separation of a protein. Because mobility depends on the size, shape, and intrinsic charge of the protein, nondenaturing electrophoresis provides a set of separation parameters distinctly different from mainly size-dependent denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis and charge-dependent isoelectric focusing. Two protocols are presented below. Continuous PAGE is highly flexible, permitting cationic and anionic electrophoresis over a full range of pH. The discontinuous procedure is limited to proteins negatively charged at neutral pH but provides high resolution for accurate size calibration.


Relevance of endoscopic ultrasound in the management of esophagus cancer therapy.
The objective of this case series study by retrospective analysis was to determine the relevance of endoscopic ultrasound (EUS) in therapeutic decision esophageal cancer. Using medical records of the Department of Endoscopy of Santa Casa de São Paulo, we have collected data from 16 patients, in 4 years, diagnosed of esophageal cancer, and presented in the form of clinical cases to a specialist surgeon in esophageal cancer and a clinical oncologist, for therapeutic evaluation before and after the outcome of EUS. Both of them choose non-resective and not curative methods (68.8% by surgeon vs. 87.5% oncologist) before EUS. The best treatment by the surgeon was chemotherapy and palliative radiotherapy associated (25%) and palliative endoscopic prostheses (25%), and by the oncologist, neoadjuvant chemotherapy and radiotherapy associated (56.2%). After EUS, the resective surgical treatment was the both choice in only 6.2% of cases, and the rest of 93.8%, non-resective. The surgeon choice was chemotherapy and palliative radiotherapy associated (44%), and oncologist choice was neoadjuvant chemotherapy and radiotherapy associated (44%). Analysis by the Chi-square method, comparing respective versus non-resective treatment, surgeon versus oncologist, with and without the EUS, obtained values of P = 0.39 and P = 0.46, respectively. The comparison between healing and non-healing treatment had the same P value. Regarding the change in behavior (resective vs. non-resective), there was a change of approach by the surgeon in 25% of cases (P = 0.17) and the oncologist moved conduct in 6.25% of cases. Comparing the changing of behavior among experts, the P value was 0.33. Despite evidence of behavior change after the EUS, the statistical point of view, the P value had no significant relevance. The main factor involved is probably due to a reduced number of sample cases. However, this is a pilot study, and is needed other with a larger number of cases. The data obtained allow us to conclude that EUS proved to be an important test for the change in staging and therapeutic management of esophageal cancer.


The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription.
Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or gynecomastia, and affected females had isosexual precocity and/or macromastia. The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old sister had precocious puberty, and their father and paternal grandmother had peripubertal gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adrenal steroid hormones were determined before and after the administration of corticotropin and/or hCG. Aromatase activity was determined by [3H]delta4-androstenedione to [3H]estrone conversion by cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphocytes and was detected by immunohistochemistry and/or Western analysis. Linkage was examined with a polymorphism of the aromatase (P450arom) gene. The P450arom messenger ribonucleic acid was analyzed by rapid amplification of complementary DNA (cDNA) ends, ribonuclease protection assay, and RT-PCR. hCG testing demonstrated a high rate of conversion of delta4-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a GnRH analog, which successfully delayed skeletal and pubertal development in both children. Markedly increased aromatase activity was found in the patients' fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom polymorphism segregated with the disease in the family. A new 5'-splice variant was present in the patients' P450arom messenger ribonucleic acid, thus identifying yet another first exon of this gene, which appears to be aberrantly expressed in this family. In conclusion, a family with the aromatase excess syndrome is described, in which the condition was inherited in an autosomal dominant manner, led to feminizing manifestations in both sexes, and was associated with the aberrant utilization of a novel transcript of the P450arom gene.


Changes in serum dopamine-beta-hydroxylase activity during group psychotherapy.
This psychobiological study investigates married-coupled group psychotherapy from pre- and postsession serum dopamine dopamine-beta-hydroxylase (DBH) determinations, the Free Association Test (FAT), and a Postsession Questionnaire (PSQ). Experimental manipulations permit controls for the assessment of DBH variations. Group, gender, and individual linear regression analyses are interpreted by a stressor-destrssor typology. DBH levels significantly increase during psychotherapy. Increments are comparable with those from physical work. Most variability in DBH is predicted from a small set of psychological variables. Psychological stressors and destressors show psychobiochemical individuality. Implications of psychological stressors for psychosomatic vulnerability are discussed.


Migraine and risk of hypertensive disorders of pregnancy: A population-based cohort study.
Migraine is associated with hypertensive disorders of pregnancy through common pathophysiological features. This study evaluates the association between migraine diagnosis and treatment, and risk of hypertensive disorders of pregnancy. We conducted a prospective cohort study in the Clinical Practice Research Datalink GOLD, a large longitudinal database of patient records in the UK. We analyzed data from liveborn or stillborn singleton deliveries from 1993-2020 with at least 24 months of medical history and no history of cardiovascular disease (n = 1,049,839). We ascertained migraine through diagnosis or prescription codes before 20 weeks of gestation and hypertensive disorders of pregnancy through diagnosis codes between 20 weeks of pregnancy and delivery. We used log-binomial regression models to estimate the risk ratio and 95% confidence intervals, comparing risk of hypertensive disorders of pregnancy among individuals with migraine to those without migraine, adjusting for confounders. A history of migraine prior to pregnancy was associated with an increased risk of hypertensive disorders of pregnancy (RR = 1.17, 95% CI: 1.09-1.26). The greatest risk was among those with pre-pregnancy migraine that persisted into the first trimester (RR = 1.84, 95% CI: 1.35-2.50). Use of migraine medication was associated with a higher risk of hypertensive disorders of pregnancy compared to non-migraineurs (RR = 1.50, 95% CI: 1.15-1.97). Results from this study indicate that migraine is a potential risk factor for hypertensive disorders of pregnancy.


[Gaucher disease: clinical, genetic and therapeutic aspects].
Gaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases for which therapy is now available. Partial deficiency of glucocerebrosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomitant anaemia and thrombocytopenia in non-neuronopathic, type 1, Gaucher disease. Severe deficiency of glucocerebrosidase caused by disabling mutation is additionally associated with neurological manifestations in the less common type 2 and type 3 Gaucher diseases. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype-phenotype relationship and the identification of modifier loci that impact on Gaucher disease phenotypes remain a critical area for research. Recombinant glucocerebrosidase (imiglucerase) is an effective mean of treating type 1 Gaucher disease and should be initiated early on in life. Amelioration of hepatosplenomegaly and of haematological manifestations is usually apparent within six months. Bone disease responds more slowly. Imiglucerase has recently been approved for the treatment of type 3 Gaucher disease. Enzyme replacement therapy cannot reverse the neurological deficits in type 2 or type 3 Gaucher disease. This should prompt further research on substrate deprivation and gene therapy.


Eliminating the domain error in local explicitly correlated second-order Møller-Plesset perturbation theory.
A new explicitly correlated local MP2-F12 method is proposed in which the error caused by truncating the virtual orbital space to pair-specific local domains is almost entirely removed. This is achieved by a simple modification of the ansatz for the explicitly correlated wave function, which makes it possible that the explicitly correlated terms correct both for the basis set incompleteness error as well as for the domain error in the LMP2. Benchmark calculations are presented for 21 molecules and 16 chemical reactions. The results demonstrate that the local approximations have hardly any effect on the accuracy of the computed correlation energies and reaction energies, and the LMP2-F12 reaction energies agree within 0.1-0.2 kcal/mol with estimated MP2 basis set limits.


Quantification of Fel d 1 in house dust samples of cat allergic patients by using monoclonal antibody specific to a novel IgE-binding epitope.
Avoidance of allergen exposure is an effective measure for preventing naÏve and allergic individuals from sensitization (primary intervention) and disease aggravation (secondary intervention), respectively. Regular monitoring of the allergens in the environment is required for the effective intervention. Thus, there is a need for cost-effective test kits for environmental allergen quantifications. To invent a test kit for quantification of cat major allergen, Fel d 1. A mouse monoclonal antibody (MAb) specific to the newly identified IgE-binding conformational epitope of the cat major allergen (Fel d 1) and rabbit polyclonal IgG to recombinant Fel d 1 were used as allergen capture and detection reagents, respectively. Native Fel d 1 was used in constructing a standard curve. Sixteen of 36 dust samples collected from houses of cat allergic subjects in Bangkok contained Fel d 1 above 0.29 μg/gram of dust which is considered as a novel threshold level for causing cat allergy sensitization or symptoms. Among them, 7 samples contained the allergen exceeding 2.35 μg/gram of dust which is the level that would aggravate asthma. Results of the allergen quantification using the locally made test kit showed strong correlation (r = 0.923) with the allergen quantification using commercialized reagents. The assay using MAb to Fel d 1 IgE-binding epitope of this study has potential application as an economic and practical tool for cat allergy intervention measure especially in localities where health resources are relatively limited.


GP2015 as a promising therapy for rheumatoid arthritis.
Rheumatoid arthritis is a common inflammatory joint disease with a myriad of systemic manifestations. Over the last 20 years its treatment has been revolutionised by the introduction of a number of different biologic drugs, including the TNF-receptor Fc fusion protein, Etanercept. However, these drugs are expensive and their widespread use puts a financial burden on healthcare systems. As many biologic treatments begin to come off patent new 'biosimilar' versions are being developed which can lead to significant cost savings. GP2015 (Erelzi®) is the second biosimilar version of Etanercept which is licensed for the treatment of rheumatoid arthritis. Areas covered: We discuss the Chemistry, pharmacokinetics and pharmacodynamics of GP2015 in relation to reference Etanercept. Preclinical trials have shown pharmacokinetic equivalence between GP2015 and the reference drug. The recently completed Phase III, randomised, double blind EQUIRA study has shown equivalent efficacy and safety between GP2015 and Etanercept in patients with rheumatoid arthritis. Expert opinion: GP2015 has shown equivalent efficacy and safety to reference Etanercept. With a growing number of biosimilar medications becoming available and another biosimilar Etanercept already being widely prescribed it is likely to be the cost of the drug that will determine if it is used widely.


Complete genome sequence of a distinct calla lily chlorotic spot virus isolated in mainland China.
The first complete genome sequence of calla lily chlorotic spot virus (CCSV) from Lijiang in northwestern Yunnan Province was obtained using RT-PCR with designed primers. The genome of CCSV isolate LJ-1-Yunnan is tripartite. The small (S) RNA is 3182 nucleotides (nt) in length and encodes a nonstructural protein (NSs, 1383 nt) and a nuclear nucleocapsid (N, 834 nt), separated by an 836-nt intergenic region (IGR). The medium (M) RNA is 4749 nt in length and encodes a nonstructural movement protein (NSm, 930 nt) and a glycoprotein (GnGc, 3,372 nt), also separated by a 349-nt IGR. The large (L) RNA is 8912 nt in length and encodes a predicted RNA-dependent RNA polymerase (RdRp, 8652 nt). The nucleotide sequences of the three viral RNA segments are 92-94 % identical to the published CCSV genome sequence, and the amino acid sequences of the encoded proteins are 96-98 % identical. However, the IGRs of the S and M RNAs are less similar, with 86 and 72 % identity, respectively. Genome sequence comparisons and phylogenetic analysis indicate that the Lijiang CCSV isolate is a unique tospovirus isolate that differs from CCSV isolates in other geographic regions.


General isotropic micropolar fluid model in smoothed particle hydrodynamics.
The smoothed particle hydrodynamics (SPH) method is used in this paper to model micropolar fluids, with emphasis on their dissipation mechanisms. To this aim, a dissipation function is defined at the particle level which depends on the relative velocity between particles but also on an additional spin degree of freedom, which modifies such relative velocity as well as introduces spin-related intrinsic dissipation mechanisms, comparable to those related to the rate of deformation tensor in Newtonian fluids. This dissipation function is then incorporated within the Lagrangian formalism, leading to a set of SPH particle equations to describe the dynamics. A continuous integral SPH version of the scheme is obtained with a bottom-up derivation which guarantees the consistency of the SPH term. The model is then enriched with two additional terms based exclusively on the spin derivatives, which grant it the maximal generality as an isotropic model for micropolar fluids. Finally, numerical verification and validation tests are documented that show that SPH is capable of accurately modeling this type of dynamics.


Perturbation Free-Energy Toolkit: An Automated Alchemical Topology Builder.
Free-energy calculations play an important role in the application of computational chemistry to a range of fields, including protein biochemistry, rational drug design, or materials science. Importantly, the free-energy difference is directly related to experimentally measurable quantities such as partition and adsorption coefficients, water activity, and binding affinities. Among several techniques aimed at predicting free-energy differences, perturbation approaches, involving the alchemical transformation of one molecule into another through intermediate states, stand out as rigorous methods based on statistical mechanics. However, despite the importance of free-energy calculations, the applicability of the perturbation approaches is still largely impeded by a number of challenges, including the definition of the perturbation path, i.e., alchemical changes leading to the transformation of one molecule to the other. To address this, an automatic perturbation topology builder based on a graph-matching algorithm is developed, which can identify the maximum common substructure (MCS) of two or multiple molecules and provide the perturbation topologies suitable for free-energy calculations using the GROMOS and the GROMACS simulation packages. Various MCS search options are presented leading to alternative definitions of the perturbation pathway. Moreover, perturbation topologies generated using the default multistate MCS search are used to calculate the changes in free energy between lysine and its two post-translational modifications, 3-methyllysine and acetyllysine. The pairwise free-energy calculations performed on this test system led to a cycle closure of 0.5 ± 0.3 and 0.2 ± 0.2 kJ mol-1, with GROMOS and GROMACS simulation packages, respectively. The same relative free energies between the three states are obtained by employing the enveloping distribution sampling (EDS) approach when compared to the pairwise perturbations. Importantly, this toolkit is made available online as an open-source Python package (https://github.com/drazen-petrov/SMArt).


Helminth parasites in Chaunus marinus and Cranopis valliceps (Anura: Bufonidae) from Lagunas Yalahau, Yucatan, Mexico.
Eight helminth taxa were found parasitizing Chaunus marinus (n = 40) and Cranopsis valliceps (n = 40) from the Parque Estatal Lagunas Yalahau, Yucatan, Mexico. Seven taxa (2 digeneans: Langeronia macrocirra, Mesocoelium monas; 1 acanthocephalan: Oncicola sp.; 3 nematodes: Rhabdias füleborni, Aplectana itzocanensis, Cruzia morleyi; and a nematode larva) were found in C. marinus, while 4 taxa (all nematodes: Rhabdias fuelleborni, Aplectana itzocanensis, Ozwaldocruzia sp., and a nematode larva) were present in C. valliceps. Nematodes, particularly A. iztocanensis, showed high prevalence, mean abundance, and mean intensity values for both species of amphibians. The occurrence of R. fuelleborni, M. monas, L. macrocirra, and C. morleyi in these amphibians from the Yucatan Peninsula confirms their neotropical distribution, while the presence of A. itzocanensis increases its geographical distribution, suggesting a preference by neotropical, rather than neartic areas.


Three component hydroxyletherification and hydroxylazidation of (trifluoromethyl)alkenes: access to α-trifluoromethyl β-heteroatom substituted tertiary alcohols.
The three component hydroxyletherification and hydroxylazidation reactions of (trifluoromethyl)alkenes are reported, providing various useful α-trifluoromethyl β-heteroatom substituted tertiary alcohols in high yields. The ipso-defluorooxylation of (trifluoromethyl)alkenes with oximes is completely inhibited. A pesticidal active compound could be synthesized with our method.


Energetic contributions of residues to the formation of early amyloid-β oligomers.
Low-weight amyloid-β (Aβ) oligomers formed at early stages of oligomerization rather than fibril assemblies seem to be the toxic components that drive neurodegeneration in Alzheimer's disease. Unfortunately, detailed knowledge of the structure of these early oligomers at the residue level is not yet available. In this study, we performed all-atom explicit solvent molecular dynamics simulations to examine the oligomerization process of Aβ10-35 monomers when forming dimers, trimers, tetramers and octamers, with four independent simulations of a total simulated time of 3 μs for each oligomer system. The decomposition of the stability free energy by MM-GBSA methodology allowed us to unravel the network of energetic interactions that stabilize such oligomers. The contribution of the intermonomeric van der Waals term is the most significant energy feature of the oligomerization process, consistent with the so-called hydrophobic effect. Furthermore, the decomposition of the stability free energy into residues and residue-pairwise terms revealed that it is mainly apolar interactions between the three specific hydrophobic fragments 31-35 (C-terminal region), 17-20 (central hydrophobic core) and 12-14 (N-terminal region) that are responsible for such a favourable effect. The conformation in which the hydrophobic cthr-chc interaction is oriented perpendicularly is particularly important. We propose three other model substructures that favour the oligomerization process and can thus be considered as molecular targets for future inhibitors. Understanding Aβ oligomerization at the residue level could lead to more efficient design of inhibitors of this process.